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Vol. 54, Issue 1, 33-43, July 1998
1
3
2 -Aminobutyric AcidA Receptors with
Flunitrazepam Identifies a Subset of Ligands that Interact Directly
with His102 of the Subunit and Predicts Orientation of These within
the Benzodiazepine Pharmacophore
Departments of
Biochemistry (R.M.M., S.F., F.E., A.A., K.Q.) and
Chemistry (I.C., H.B.), Merck Sharp and Dohme Research Laboratories,
Harlow, Essex, UK CM2O 2QR
Photoincorporation of ligands into the benzodiazepine site of native
-aminobutyric acidA (GABAA) receptors
provides useful information about the nature of the benzodiazepine (BZ)
binding site. Photoincorporation of flunitrazepam into a single
population of GABAA receptors, recombinant human
1
32, was investigated to probe further the mechanism and
orientation of flunitrazepam and other ligands in the BZ binding site.
It was concluded that the receptor is primarily derivatized with the
entire, unfragmented, flunitrazepam molecule, which undergoes a
conformational change during photolysis and largely vacates the
benzodiazepine binding site. Investigation of the BZ site after
photoincorporation of [3H]flunitrazepam confirmed that
binding of other radioligands was unaffected by incorporation of
flunitrazepam. This did not correlate with their efficacy but depended
on the presence of particular structural features in the molecule. It
was observed that affected compounds have a pendant phenyl moiety,
analogous to the 5-phenyl group of flunitrazepam, which are proposed to
overlap and interact with the same residue or residues in the BZ
binding site. Because the major site of flunitrazepam
photoincorporation has been shown to be His102, we propose that this
group of compounds interacts directly with His 102, whereas compounds
of other structural types have no direct interaction with this amino
acid. The orientation of ligands within the BZ binding site and their
specific interaction with identified amino acids are not well
understood. The data in the current study indicate that His102
interacts directly with the pendant phenyl group of diazepam, and
further implications for the pharmacophore of the BZ binding site are
discussed.
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